Production of 7-dehydrosterols



triethyl amine, N,N-dipropylaniline,

Fatentecl Mar. 27, 1951 UNITED STATES PA T OFFICE I PRODUCTION or flfi firpnosrmots I Kurt H. Schaaf, Jamaica, N. Y., assignor to Nopco Chemical Company, Harrison, N. J a corpora tion of New Jersey No Drawing; Application May 14, 1949,

Serial No. 93,409v

Part of this work has been directed to the production of 7-dehydrocholesterol. As is well known, 7-dehydrocholesterol is readily converted to vimain D3 by irradiation with ultra-violet light. In order to form 7-dehydrocholesterol from the halogenated cholesterol compounds produced in accordance with the Ziegler process, fitis necessary to subject the halogenated sterol "compounds to dehydrohalogenation with a suitable dehydrohalogenating agent. The com-.

pounds which have been most frequently employed to react with the halogenated sterol derivatives. to eifect dehydrohalogenation are compounds such as dimethylaniline, diethylaniline, collidine and quinoline. Compounds such as N-ethylpiperidine and N,N-diethyl-cyclohexyl amine have also been employed for this purpose. Of

these many prior art dehydrohalogenating agents, it has been my experience that diethyl aniline has been by far the most satisfactory and: has given the highest yields and the highestpurity as compared to any of the other compounds above mentioned. In BritishPatent- No. 574,432, the results which are set forth therein appear to indicate the same result, 1. e. that diethylaniline is: by far the most satisfactory dehydrohalogenating agent so far known; Although diethylaniline has proved to be fairly successful in the prior art as a dehydrohalogenating agent, the'yields of 7-dehydro compounds which are obtained even whenit is employed as the dehydrohalogenating agent are 17 Claims. *(01. zen-397.2)

halogenati igv halogenated sterol compounds which will give much higher yields than the prior artmethods for dehydrohalogenation and which higher yields will be of products having a purity higher than the products obtained by the prior art dehydrohalogenation processes.

Other objects of the invention will in part be obvious and will in part appear hereinafter.

,I have dis-covered that the above and other objects of the invention may be realized'if the dehydrohalogenation 'of 'a halogenated sterol compound is effected by reacting the halogenated sterol compound with quinaldine in the presence of :an aromatic hydrocarbon solvent. The yields of thedesired '7-dehydrosterol compounds which are obtained: are substantially higher when the dehydrohalogenation is efiected in this manner than when the dehydrohalogenation is carried out in accordance with the disclosures of the prior art. Furthermore, the products which are obtained in -these substantially higher yields are often of considerably higher purity than-the products which are obtained when the dehydrohalogenation-is carried out in accordance with the methods'of the prior art.

- Asl have stated above, it is possible to obtain much higher. yields of the desired 'Z-dehydronot as high as desired. Furthermore, the purity sterol compound by effecting the dehydrohalogenation of the halogenated sterol compound by reacting the halogenated sterol compound with quinaldine in' the presence of an aromatic hy-.- drocarbon solvent.- As will appear from the various specific examples given hereinafter, the yields obtained in this manner are often well over 100% reater than the yields obtained when the dehydrohalogenation is carried out in acff cordance with the prior art methods. When dehydrohalogenation is effected with diethylaniline (one of the prior art dehydrohalogenating agents) in the presence of an aromatic hy-. drocarbon solvent, the yields which are obtained are no, greater and in some cases are. even less than the yields obtained with diethylaniline in the absence of such a solvent. Undoubtedly this is the reason'why itis recommended in U. S. Patent No. 2,441,091 that dehydrohalogenation. should'be carried out in a solvent-free medium; In addition to the much higher yields of the tie-1 sired products which are obtained with my novel process as compared to theprior art methods} thepurityof the products which are obtained.

by my process is in nearly all cases higher than the purity of the :products resulting from the prior ,artprocesses. H v M l Thea-mount of quinaldine which is employed 3 in the reaction should be suflicient, of course, to react completely with the halogenated sterol compound which is to be dehydrohalogenated, i. e. at least a mole to mole ratio should be employed. As a matter of convenience, it is usually preferred to use an excess of quinaldine over the amount theoretically required to bring about the? dehydrohalogefiation reaction. Thus from about three moles to about six moles of quinaldine per mole of halogenated sterol compound are conveniently employed. Larger. amountsof quinaldine per mole of halogenated sterol compound may be employed, if desired, but the of such larger amounts is not necessary. In order to obtain the most consistent results, it is pre- I ferred that quinaldine in a fairly h'igl'f state of purity be used. Commercial quinaldine can be purified by fractional distillation or quinaldine can be synthesized by a modified sliiaufi syn thesis. In both cases the quinaldine is of a, suitablestate'of purity and ill cofisistentlyeii cellerit re s when employed to riiigabout' he dehydrohalogfenatioh" of a halogenated steroicoin pound Iraenie, however, quinaldine egfih tain'in'g" rather high percentages of impurities can be empm d sinc fu y in the process or the invention. As will appear from certain of the specific eiiamples given hereinafter; quinaldine eont'aining as injuch as 19% arid more of impuriti can be used successfully to meet the d'ehy-' log'eha'tion of the halogenated s teifol c0151 po as without appfecilably dcreasing the yields of the" desir'ed t-dehy rosterei co ipo'nds'.

"invent halogenated fs' terol derivativ' afid' he Ainofrg the such hydro 643 15 times as greet the volume'of the animal:-

entptv qu eld e e e was id 1 i. te employed althoughsuch higher ratios are net e ses-i In ca yifigo f pro theinvention it is iflces a v i ld e; solvent, and ha dg'nated 4 r p drto bring about the defiydrohalo'genation 1eactiofi. In most cases, it ispr f rr'd to heat Qereaetion mixture atthe refiuk temperature of th eye are solve'iitest em j r fins t high'' ti yields obtained when re'actionlis carried out a; tempe ature between out 80 o. and about 150 c; although temper-'- at es highrtha-n 150? C'; n be employed desired, The ieng or time when; its necessary ts heat the ractloii mixture win vary slightly depending upon the terhpratlirat Whih the re action iscarriedout matte longest periods of ng being requires at the iewer temp-ere- I ave found that eii'elli-it yields 6': the "d '7- 1hy'dib comp may be Obtained S?) I e s aft 1" peri ds f Beating as short as (See-quarter of an hear} g.- when Xylene is the at the remix temperature of the selvent, a1-

though in other cases, e, g. when toluene is the aromatic solvent, it appears to be desirable to heat the reaction mixture at the reflux temperature of the solvent for at least one-half an hour. In all cases, excellent yields of the desired compounds will be obtained.

After the dehydrohalogenatioh reaction has seen accomplished, the" desired 7-de'hydrosterol can be recovered from the dehydrohalogenation reaction mixture in any convenient manner.

The exactmethod employed for isolating the 7-dehydrosterol compound will depend to some extent the" specific derivative of the sterol empibyeaas he starting material in the proc- \v'ri-at appears ilile practice ylgroup to an ester-group an ffioir'it esternyin g agent such as acetic a snare, ben zoyl chloride", if the s i'olco iiptfiid has seen thereof, the sterol is y .ysis of the ester ere p by septa-incense wen aieenolie alkali. The practice in the art shown by the British ea referred t hereifialdov'e' ar-id' by U. S. Pat- 2,441,091 a; its counterpart, renen; Patel; No, 961,551,- nas seen to remeve the dehydroli'alogenatirig agentfroifi the reac use mixture peer to" e iiig out 'th sapefiihew men of the ester of the ste oi compo-1i d; This is aeemensiiee to these prior art patents either a pleases involving admixing the feat ti''fi mix-ture excess of aqueous acid so'l an ex ingthis; ni-ixture with a solvent 'Suo'hether or a hydrocarbon solvent to re""cive the vmydr'osterei ester from the rests ifii trim or it 'iS- accomplished by rocess ir'-' volving dissolv the dehydro'ha'iogenatiorr re a an excess of-a'waterimmiseible solv "t such as petroleum ether and then ex tia'c'tl' that solvent solution with an aqueousacid sciatica to renews; the; deh-ydrohalog-enating agent from the solvent solution; In either case the solvent solution containing the 7=olehydro= ste'rol ester is then Washed with a dilute alkalisolut'ion to retrieve any acid dissolved 'in the sblv'e'nt and the'i'after the sol-vent solution is washed with water to remove any alkali dissolved the'solvent. Thereafter, the solvent is generally evaporated to recover the l -*dehydro'st'erolester since the solvent which has been used in separating the ester from the dehydrohalogen-ation reaction mixture is generally solvent which is not Wei-1 suited a vehicle in which to carry out the saponifieatioi i of the ester to form the free sterol. After the ester has been isolated it is then hydrolyzed with an alcoholic alkali solutioii; In certain of the specific :e am les given h'e'feil'iaftl', "the general procedure of the prior art is employed to separate the cr ude' l 'dhydio sterol esters from the 'dehydi'ohal'ogenation reactio'ii mixture. prior. to sapomneaummf theesters.-

by teatime-tree tifitli In these particular experiments it was desiredto out the saponification of the esters in accordance with the new and highly improved process which is disclosed and claimed in my copending U.- S. Patent Application Serial, No. 781,497 filed on October 22, 1947. The details of this process are set forth herein in Examples X and XI. This processeliminates entirely the separation of the 7'-dehydrosterol ester from the dehydrohalogenating agent prior to effecting the saponification of the ester. Instead the saponification iscarried out directly in the reaction'mixture'obtained from the dehydrohalogenation reaction objects ofthe' inventiomreference may be had by dissolving the dehydrohalogenation reaction mixture in an excess of an alcoholic alkalisoluw the sterol compounds during the halogenation reaction by converting the hydroxyl groupto a groupwhich will not react with the dehydrohaloge'nating agent but which may later be re converted to the hydroxyl group. For convenince, the term"inactive group will be used herein in referring to such a group; For the purposes of the presentjinvention, it is, of course, entirely immaterial just'what inactive group is used to protect 'the 3-position of the sterol compound since the reaction between the halogenated sterol compound andthe quinaldine involves, of course, the removal of the halogen atom from the 7 position on the sterol compound and the removal of; the hydrogen atom from the 8 position of the sterol compound. f specific examples given hereinafter show the juse of the halogenated acetate and benzoate esters of chloesterol in the process of the invention. These examples are onlyillustrative and thire'action which takes place between these halogenated esters and quinaldine takes place with equal efiiciency and ease between quinaldi'iie and any other sterol compound having a double bond between the '5 and 6 carbon atoms and a halogen atom on the 7 carbon atom; Thus the process of my invention is quite suitable for and is very effective in dehydrohalogenating any sterol compounds v of this nature regardless of whether they are the esters, the ethers of any other suitable derivatives of the particular sterol the} various sterol esters'which may be formed can be dehydrohalogenated by the process of myto the following examples which are given merely as further illustrations of the invention and are not to be construed in a limiting sense:

I Example I A mixture of 10.0 gms. of crude 7-bromocholesteryl'benzoate and 15 mls. of diethylaniline (one of the prior art dehydrohalogenating agents) was heated on an oil bath for 3 hours at 95 C. with stirring in the presence of a nitrogen atmosphere. The reaction mixture was cooled, taken up in 75 mls. of 5% hydrochloric acid and extracted twice with ml. portions of benzene. The benzene extracts were washed to neutrality with three 25 ml. portions of water. To the benzene'solution there was addedagsolution of 2.0 gms. of 86% KOHpellets in 40;m1s. of ethanol. The mixture was refluxed for one-half hour in the presence of nitrogento hydrolyze the '7-dehydrocholestery1 benzoate to 'l-dehydro cholesterol- The cooled reaction mixture was poured into 150 mls. of water and the resulting mixture was extracted with four 50 ml. portions of ether. The ether extracts were washed with three 50 ml. portions of a 10% salt solution, then dried over sodium sulphate and thereafter the solvent was removed in vacuo. A lighttan solid weighing 7.05 gms. was obtained. A spectrescopic analysis of this material showed thatthe product had a purity of 26.2%, thus giving a yield of 7-dehydrocholesterol based on the amount of 'I-bromocholesteryl benzoate em-, ployed of only 27.4%. I

4 Example II To a boiling hot mixture of 15 ml ofaquinaldine and 50 ml. of toluene was added'a solu-.--

tion made up of 25 ml. of toluene containing 10 gms. of the same crude 7-bromocholesteryl bell-r; zoate employed in Example I. The mixture was refluxed forr2 hours in an atmosphere of nitrogen. At the end of the reaction, the mixture was chilled and filtered with suction. to remove invention. Among the sterol esters which have I the quinaldine hydrobromide which was then washed with'a small amount of ether. The com; bined ether-toluene filtrate was washed once with 75 ml. of 5% hydrochloric'acid. The aqueous acid phase was then extracted twice with 50 ml. each of ether. Thecombined ether-toluene filtrateand' washings were washed with two 50 m1. portions of water, and the solvent was evaporated under vacuum. The residue was dissolved in ml. of benzene andthe crude 'l-dehydro. cholesteryl benzoate was thenhydrolyzed and the '7-dehydrocholesterol recovered as described in the previous example. A creamy solid weigh: ing 6.61 gms. was obtained. Spectroscopic anal ysis of the product showed a purity of 63.4%, thus giving a total yield of the desired product of 62.1%. Thus it is seen that based upon .the purity of the product obtained in accordance with the prior art process, the purity of the prodnot of the present example was over 140% greater than the purity of the product obtained when diethylaniline *was employed as the dehydrohalogenating agent. Likewise, the total yield of the desired product in this example was over greater than the total yield obtained with carried out in the presence oi xylene.

. scopio: analysis; it was; found to? have a purity of cum-erases: thus: giving: a total yield: of 'l -dehydroc'holesterol: Ofi only; 2413 experiment. with". that.- of. Example: 1,. it is seen that the toluene:- instead. of: causing the. diethylaniline to give improved yields, caused the: yield of: 7-dehydrocholesterol. produced to drop by abouti11=%:. Thusit-appe'ars; that the combine. tinn: of. are aromatic: hydrocarbon: solvent" anddiethylaniline is not as efiective; a dehydrohalogenating. agentasis: diethylaniline alone;

ErdmpZeIV Another experiment'was carried out in a: manner? similar to thatvemployed inExample-IL In this experiment ahot solution of 10. gms. of. crude 7-bromocholesteryl benzoate in. toluene was; added' to a hot mixture of 15 ml. of quinaldinein toluene. The total amount of toluene employed was- 75 mls.. The mixture was heatedaatthe reflux temperature of thetoluene for /2 hour. The Z-dehydrocholesterol was isolated. from the: esterthereof as in the previous examples and: recoveredin-the same mannor as before. The yield obtained amounted to L07 guns. of a yellow solid which on spectroscopic'. analysis was. found. to have a. purity of. 55% thus giving a total yield; of: l-del'iydrocholesterol of 57.6%.

Example V this experiment, crude 7hromo'cholesteryl henzoate was dehydrohalogenated with quinaldine' in the presence of benzene. The amounts oftherea'gents were the same" as in the previous examples. The reagents in. this experiment were admixed at room. temperature as in Example I; The mixture was heated under reflux. for 4 hOUIS OII a; steam bath. The T-dehyd'rosterol ester was hydrolyzed and the free 7-dehyd'ro- 'sterol recovered as in the previous examples.

yield of 7.25'gms. of. a pale tan solid was obtained. This product on spectroscopic analysis was: found to have ajpurity' of 5318 thus giving a. yield. of 5718 of 7-dehydrocholesterol'.

Example VI this experiment the reaction of crude 7' lbrom'ocholesteryl benzoate with quinaldi'ne was The reagents were used in the same amounts and were admixed in the same manner as in Example IV and the reaction was carried out at the reflux temperature: of the xylene for 2' hours. The crude 7-dehydroch'olesterol which was obtained amounted to 6.60" gins. of. a light orange-yellow solid having apurity; of 57.4% thus givinga; yield of 56.1%..

Example VII In: this experiment-the procedure of Example was followed in all respects except that the reaction period instead of being 2 hours as in Example VI was reduced to 1 minutes. The product which was obtained was in" all respects essentially the same as that obtained in Example VI. A light orange-yellow solid weighing 6.54 obtained. Itzhad a purity of 568% thus givinga yieldof. l dehydrocholesterol of 55.0 It is apparent" therefore that it is unnecessary to Comparing; this 8: heatthe. reagents for. more-thanabout minutes inprder to;obtainsubstantially completereaction whenthe reaction-iscarriedoutiin a-Xylene sellition. Itis also. apparentthatperiods of. heating substantially inexcess of 15 minutes. appear to. have: nodetrimental effects: when the. reaction) is carried out with. quinaldine. inthe presence of xylene. at the. reflux temperature of the. xylene:

Exam le VIII! Another experiment was carried out wherein 1U gmsLof crude. 7-brcmocholesteryl benzo'at'e was reacted? with quinaldine in the presence of tolu ene. In. this. experiment mls. of quinal'dine were employedinstead' of'I5 mls. as-in the'pnevifous experiments, and. T mls. of toluene were employed instead" of? mls. of solvent as the previous. examples. The reagents weretmixedttrgether at. an elevated temperature as inExample IV andiwere. then heated for 2 hours at therefiux temperature of the solvent. A creamy's'oliil amounting 110 6.76. gms. was recovered bythesam'e. procedure which was employed in the previous examples to isolate the 7-dehydrocholesterol. The product had a purity of 61.9% thusv givinga total yield. of 7-dehydrocholesterol' of6119'%.

Example IX In this experiment I0 gins: of thesame crude 7-bromocholesteryl benzoate as was employed. in Example I were reacted with" 15 mls. of. qui'naldine in the presence of 300 mls. of xylene. Thereagents were mixed together at room temperature and. then heated for 2' hours at the refluxteniperatureofthe-xylne; The 7-dehydi'ocholes-terof Was isolated in the same manner as in the'previ olls examples and; amounted to 7181' gmsf of a light tan solid having a purity of 63.6% thusgiving a yield of 7-dehydrocholesterol of 735%. From the resultsof this experiment itis apparent that a ratherlarge' excessof the aromatic-hydrocarb'onsolvent appears t6 have a substantial beneficial efiect in increasing the total yield of 7-dehydrosterol. It is seen that the yield in; this examplewas from about 270% to about 300% of the yields obtained in experiments I and in which diethylaniline was employed to'react" with the halogenated cholesterol esters inprder to eifect the dehydrohalogenation reactiom Furthermore the purity of the crude product'which was obtained in the present examplewas about two and a halftimes as great as that of the prod?- ucts obtained in those experiments in which diethylaniline was employed to effect thedehydrohalogenation.

Example X To a boiling hot solution of 2000 gmsi "or recrystallized 'cholesteryl acetatein 8- liters of ate hydrous hexane there were added 9.30 gms. of lauroyl peroxide and 1 040 gm'S; or powdered, crude 96.05% N-bromosuccinirnide- The-halo 'genation reactiontook place over a period 'of" I 3" minutes after which'the reaction mixture was cooled to about 55 C. and filtered with suction;

-The succinimide which was filtered off was washed twice with 500 ml. portions of hexane. The filtrate and washings were combined and'S liters of dried diethylaniline. (one of the-'priora'rt dehydrohalogenating agents) added thereto, yielding amixture weighing 10,821 gms.

971 gms. of the mixture were heated in a water bath in vacuo (N2 atm-Jlto distill ofi the hexane. The residual diethylani-line solution thus-obtainedwas heated at C.91 C. at 40 mm. pressure for v 3 hours with stirring (Na atm-J. T0 the reaction mixturexthere was thenadded a hot solution of 79.4 gms. of, 87% KOH pellets in 825-ml. of ethyl alcohol and the mixture refluxed in a water bath -ior one-half-hour with stirring (N2. atm.). The reaction mixture was then chilled to +4 C. with stirring to crystallize the 7 -dehydrocholestero1.

. Then 120 ml. of water were slowly added and the 'mixture stored at +2 0. overnight.

The solids were filtered off at room temperature and washed first with four 150 ml. portions crew .water and then with two 100 ml. portions of icecold 85% ethanol. The crude, crystalline 7.-dehydrocholesterol was dried at 105 F. in a vacuum drier and yielded 99.9 gms. of a dark-cream, crystalline solid.

From a spectroscopic analysis the following results were obtained:

54.4% purity 1 30.25% overall yield from cholesteryl acetate.

Example XI To a boiling hot solution of 200.0 gms. of recrystallized cholesterylacetate in 800 ml. of anhydrous hexane were added 102.0 gms. of powdered, recrystallized 97.4% N-bromosucc-inimide and 0.930 gms. of lauroyl'peroxide. The broinit ation was conducted as in Example X, and the reaction mixture was then filtered to remove the succinimide. The hexane of the filtrate was evaporated in a water-bath (55 C.) in vacuo "(N2 atm.). The amberresidue was dissolved in 250 ml. of anhydrous toluene, and the solvent wasfevap'orated as above to-flush out any residual hexane. The residue was then dissolved in 1500 ml. of toluene,- and 300ml. of quinaldine was added. Themixture was refluxed (N2 atm.) for "two hours with stirring, and the toluenewas then evaporated in a water-bath'(85 C.) in vacuo (N2 atm.).

"The remaining, dark-amber reaction mixture was refluxed (N2 atm.) for /2 hour with a solution of 79.4 gms. of 86% KOH pellets in 825 m1. 'oiethyl alcohol. To the chilled mixture was added 120 ml. of water, and the resulting mixturewas stored at C.

The crude 7 dehydrocholesterol, which was isolated in the same manner as in Example X,

amounted vto 130.7 gms. of a light-tan solidp A spectroscopic analysis of" this product gave the following results: I

66.6% purity 48.5% overall yield from cholesteryl acetate.

' Example XIII "To determine the effector the purity of the quinaldine uponthe yield of, 7-dehydrosterol which could be obtained, a number of experimentswerecarried out using samplesiof quinwhichkwere obtained were.61.1%, 56.5%, 57.0%

and :50.6,%.. Thus it is: seen that: although the ods.

actants, saidreaction being carried out by hefa;

purity and yield of the products obtained are slightly higher whenflthe quinaldine contains only a small percentage of impuritieszas compared to when it contains a relatively large percentage of impurities, very excellent yields of a product having, a relatively high degree of purity are obtained even when the quinaldine does contain a relatively large percentage of impurities. e

From the illustrative examples and the. general description of the invention given hereinabcve. it is quite apparent that the process of my invention gives far greater yields of the desired 7-dehydrosterols than can be obtained when operating in accordance with the prior'art meth- Furthermore the products'which areobtained by the process of my invention oftenhave a -much greater puritythan the products'ob-' tained by the'prior art methods. Althdughtlile detailed examples given hereinabove have dealt with the treatmentof esters of cholesterolitl're process of my invention'can be applied to the treatment of any esters of any similar sterol or to any other sterol derivative in whichthe 3 position is protected by some inactive-group on the 3 position other than an ester group such as. for example, an ether group. The particular inactive, group which isat the 3 ,'positio l to protect that position from attack throughout I the process of converting the sterolto'a'FI-dehydrosterol .is entirely unimportant as "faras, the process of myinvention is concernedfinasmuch as the particular group fwhich is on'the a position in no way enters into the, reaction which occursbetween the halogenated sterol compound and uuin'aldine. Consequentlythe process of my invention is applicable to the dehydrohalp'gei ia tion of any sterol derivative having a double bond between the 5 and 6 carbon atoms and having a halogen atom on the 7 carbon atom."

The process of halogenating a sterol derivative with a compound such as N-bromosuccini mide in the presence of an organic peroxide,

which process was employed in Examples X and XI to prepare the halogenated sterol deriveatives, is disclosed and claimed in copei-iding U. s. Patent Application...Serial No...765.,631- of William L. RuighfiledpnAuguSt 1 .11941 1 Having described my invention,- what I- claim as new and desire to secure by Letters Patent is:

1. In a process for producing a7-dehydrosterol, the step which comprises reacting quinaldine with a sterol derivative selected frornthe group consisting of sterol esters and sterol ethers which have a double bond between the. 5 carbon atom and the 6 carbon atom and which has a halogen atom attached. to the 7,carbon-atom with the reaction of the quinaldine with thehalogenated sterol derivative being carriedout in'an inert aromatic hydrocarbon solvent solutionor the r ing the solution oi the reactants at a te'mperaf ture of at least about C. f I

2. In a process'for producing a 7-dehydrosterol, the step which comprises reacting quinaldine with a cholesterol ether which ha s a'double bond b etween the 5 carbon-atom and the-6 carbon atom andwhich has a halogenatom-attached tothe 7 carbonatom'witlithereaction of the quinald-ine with the halogenated sterol derivative being car ried out in an inert aromatic hydrocarbon s 0l' vent solution of the reactants, said reaction being 'c'arriedsout by' heating the solution of thefrefactants at temperatureof at least ab01It80"-C.-

' ffor producing amQen-Ycmalm, instep no,irrprises :quina'idine with la-stei'ol ester which {has :ardouble ibond :be ftween ft'he -15 carbon atom :ran'd the t 6 marbon atom and which has za -halogenatom attached 2to the 7 carb on:atom iWit'h ithe :reaction of ithe 'ouinaidine with :theJhaIogenated sterohderivative being :carnlied out in an inert aromatic hydrocarbon F501- vent solution of the reactants, said reactioniloeing .carried rout byheating the$l11ti0n of :the ;react I zantstat artemneraturerof -at?least;about-fi0*0.

1 47. jzlna process ionproducingl-a 'Y-diehydrosterol, ighe :step which :comhrises reacting 'quinaldine with I an ester f -echoiesterol which :has :a double hand between :the ioa-rboniatom and the :6 teariboniatom tandwhichihas-aihalogexratomattached ate :the carbon atom with the irea-otion (of the guinaldine zvvithw-thedifilogenated sterol derivative gbfiil'gglga'riiied out inian inert aromatichydrocar- (bon solvent solution Lof the reactantaesaid =reac-- tion being carried :out by heating the solution -.-of the =reaotants at .-a temperature of at least aboutabflC.

l5, In;alprocesslfcr producinga H-qiehydrosterol, the ,Step which .cornprises reacting ouinaldine .with ,a .benzoate esterloi cholesterol which .has a double bond'betweenrthefi lcarbonatom and the ,6 carbon.atoinanrl whicnhastalhalogenl atomatitaehed .to $13118 f7 .carboiratom \with the .reactionof the guinaldine with {the halogenated sterol .,deli lative heing married -out .in an inert (aromatic hydrocarbon solvent solution .of the ireactants, id reaction bein -.oarried \out [by heating the tion softhe reactantsiat-iatemperature oflat ileas aboutenlq g 5- 1.11: apmcessi mm ucia a.wlehyxlmste el the tep wh ch com rises reamin :quiealdin ywithi'an acetate ester of ,oliolesterol vWhich has {a double rhond Ibetvceen the 5 .carhon atom and thefi carbon atom and whifihvhasaihalogenatom on ithe 7 carbon atomwith the reaction ,ojrthe ion :of "the sat at 'eraturezojfatl'leastgahout w"B.

:10. in "a 1 process zfor e roducing i131 fl-: dehyd-recsterol, :the step which:comprises reacting equinaldine with aoholesterol ether-whichihasa double bond "between Line -5 carbon .atom and Lthe ?6 rearbon atom and which has'a'haiogen atom attached to the '7 carbon :atom with the reaction :of the lquinaldine with :the l-ralogenated -cholesterol -derivative I'being carriejdbut in a toluene solution 'of the reactants, :sa'id reaction 'being carried -;.out --by heating the solution of the reaotantsata temperature: of at least abou.t:80 C.

111. In a process for producing a ihdehydrosterol, the step which comprises reacting quinamine with a cholesterol ether :Whioh has a double bond between the 5 caiibon -atom and -the 6 carbon atom and which has a halogematomat tachedto the :7 ..carbon atom with :thereaction :of the quinaldine with the halogenated cholesterol derivative being carried out in a xylene solution of the reactants, said reaction b eing iearried :out .by heating :the solution :of the zreaoamts at a .rtemperaturelof atleastaboutsO" C.

;-l-2. .=In a process for producing --a 'l-idehydro- ,sterol, the step {which comprises reacting 1 quinealdine with (an ester .of {cholesterol which :has :-a double bond between the -5 carbon atom and the of) .carbon :atom and which has a halogen ;.atom attached to-the lcarbonlatom with the reaction of the ouinaldinewith ltheihalpgenated cholesterol ,iderivative abeing carried out in a ,henzen lsolu- :tionof the lreactantssaidireaction being-harried -:;eu,t by heating ithesolutionlofuthegreactants at quinaldine with vthe halogenated sterol derivative being carried 7 outin an inert aromatic hydrocariJoon solvent solution of .the reactants, said ,re-

act o "bei carried out by heating'the solution qi eit'h sol t o of t e reactan s at :a tem at ia i afita out 80C. :8-111 '-a'pm iqrle dueinea"hdeh o th s ep w i oomnris s ea ting hu n din with F bromoghdlesteryl acetate with the -reacnot of the uinaldin w th t e 'jha ee n ratx01 derivativ "being carried out ,in 311.",111e1t aromatic hydrocarbon solvent; solution of the re-- ac'tants, said reaction'being carriedoutgbyheating -the solution of the reactants at .a temperature of.at1east,about,80 C. a Y

J .9. Joe process,ior producinga c'l denydrosterol, the step Wh h Qm iises a ins qu nald n w th arho est 'e ethe whi h esi uble n :hetween :the ioarbon atom and :the 26 carbon atom a d which h s a :heieeenet m ttach d $02, .18 carbon. atom with the reaction of 'ithe vguinaldine with the halogenated :choles-terol .de- .rivative being married gout :in benzene solution of :the :reaetants, said reaction being zcarried tout .axtemperature fiat least about. 3041.

1 13.111 la nrccess ior producing .-a fledehydrosterol, the step which oomprises areacting rquin- .aldine with an ester .of cholesterol which has ;a

double bond between the 5 carbon atomra-nd the ,6 carbon atom and -lwhich has .a halogen atom attached ito the 37 carbon atom with there-action ofithe guinaldine withttheihalogenate d. cholesterol derivative heingvcarried out in .a toluene solution of vthe reactants, said l reaction being carried outby heating the solution of the ,reactants at .a lteinperaturerof at least, about; .C.

14. .In a process for producing .a 'J-fiehydrosterol, ;the .step which comprises reacting quinaldine with an ester of cholesterol which .a double bondbetween the 5 carbon atom andthe 6 carbon atom and which has a halogen atom attached to the 7 carbon atom with the-reaction of the quinaldine with "the balogenated cholesterol derivative being carriedoutiin a Xylene solution of the reactants, said reaction being carried out hylheating thesolution-iojfithe rireactantsata -temnera u e-of a leastabQutBMC- 51.5. .;In @a process for :oroducing a ifledehmmsterol, ithe which comprises ateaoting uin- .aicline with fl-hromooholesteryl :acetate ;wi.tn the reaction .rbei ng carried out in a benzene solution of the :xeactants, said :reaction being carried out byheatingvthe solution 10f the reactants ;at a temperatureaofatzleastabout-80C.

5:6.l1n .a process for :producing a 7-+dehydro- .sterol, ithe step which comprises rreacting quinaldine awith 7 +hromucholesteryl vbenzoate-wi :11 the reactionmeingmarried'outiinatoluenesolutionof themeacitants, --said:reacti0 n :heing married .out by heating ithe :solution :of atthe reactants at a temneratureiofiatleast about:80: C.

.17. :In :;a process for :producing a -7-dehydro stero1,'the FStQpWVhiCh acomprises reacting quinaldine with'fl-bromocholesteryli benzoatewithth'e reactionsleeingecairiedsout inta fxylfihe solution of 13 the reactants, said reaction being carried out by Number heating the solution of the reactants at a 'eem- 2,341,733 perature of at least about 80 C. 1 2,441,091

, ,44 KURT H. SCI-IAAF. 5 2,476,424,: REFERENCES CITED The following references are of record in the Number 'file of this patent: 500 353 UNITED STATES PATENTS 10 Number Name Date 2,023,075 1 Harris Dec. 3, 1935 2,255,815 Rosenberg Sept. 16, 1941 Name v Date Meuly 1 Feb. 15, 1944 Van der Wiet et a1; 1 May 1948 Butenandt May 18, 1948 Lowenbein July 19, 1948 FOREIGN PATENTS Country Date Great Britain Jan. 31, 1939 

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